The mortality induced by graft-vs.-host reaction (GVHR) in (DBA/2 x B10.D2)F1 recipients transplanted with cells from H-2d-identical B10.D2 donors can be abrogated by preimmunizing the donors with parent-strain spleen cells from normal DBA/2 mice. The experiments described here were designed to explore the possibility that the observed protection might be mediated by veto cells contained in the immunizing cell inoculum; the reasoning was based on an analogy with the cytotoxic T lymphocyte response to non-H-2 antigens where suppression can be mediated by veto cells, present in the spleens of normal mice, which are radiosensitive and largely Lyt-2+. We show that the intensity of the protection against GVHR mortality is a function of the immunizing cell dose, and that protection remains effective when optimal doses of immunizing cells are (a) irradiated or (b) pretreated with anti-Thy-1 serum. GVHR suppression is abrogated when, before transfer to F1 recipients, suppressor cells from spleens of immunized donors are pretreated with antiserum directed against Lyt-1.2 (expressed by B10.D2 but not by DBA/2, which expresses Lyt-1.1); in contrast, it is not significantly affected when these same cells are pretreated with anti-Lyt-2.2 alloantiserum. We conclude that when the antigen load is great enough the immunizing cells play a largely passive role in the observed suppression. The protection against GVHR mortality seen in this H-2-compatible combination is transferable by Lyt-1+2- suppressor T cells originating in mice given high doses of alloantigen. These suppressor cells are therefore distinct from the splenic veto T cells effective against cytotoxic T lymphocyte responses to non-H-2 antigens. The mechanism of the observed suppression and its relationship to Mls product(s) are discussed.
